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PSEN1 is one of four core proteins in the -secretase endoprotease complex that performs intramembrane cleavage of dozens of integral membrane proteins, including -amyloid precursor protein (APP) that sequentially generates the -carboxy-terminal fragment (CTF) and amyloid-, two polypeptides implicated in AD pathogenesis Ryanodine receptors (RyRs) Ion channels residing in the sarcoplasmic/endoplasmic reticulum membrane and responsible for Ca 2+ release from intracellular stores in excitable tissues, such as muscles and neurons Tau (MAPT) A group of six highly soluble protein isoforms produced by alternative splicing from MAPT that help stabilize the microtubule cytoskeleton of neurons and compose neurofibrillary tangles, a hallmark of Alzheimer disease (AD) TFEB, TFE3 Members of the MiT-TFE family of helixloophelix leucine zipper transcription factors that regulate expression of genes involved in the biogenesis and function of lysosomes and autophagosomes Footnotes Competing interests D.C.R

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Early-phase studies showed that CB-839 is safe and well-tolerated in solid tumors with promising signs of clinical activity in multiple tumor types including triple-negative breast cancer, NSCLC, and mesothelioma

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There are four main consensus molecular subtypes: CMS1, CMS2, CMS3, and CMS4 (8)